At the initial application five years ago, we had identified the first known prostaglandin (PG) and thromboxane (TX) transporter, which we named "PGT". With this grant we have found that PGT has a substrate specificity consistent with signal termination via PG uptake, and that it is likely a lactate/PG exchanger, and so is poised energetically for PG uptake. One puzzle, however, has been that PGT protein is expressed strongly in cells that synthesize and release PGs. We now propose a new hypothesis for the cellular control of PG release using PGT: 1) In cells synthesizing PGs, efflux across the plasma membrane occurs by unregulated simple diffusion. However, control of net PG/Tx release is achieved by regulated PGT insertion into the plasma membrane, causing PG reuptake into the cell without intracellular oxidation. 2) In cell types that oxidize PGs, PGT mediates constitutive signal termination via uptake and oxidation. We have evidence for this model: cultured rat renal medullary interstitial cells (RMICs) express PGT. Exposing-RMICs to hypertonic medium causes rapid down-regulation of (PGT-mediated) 3H-PGE2 uptake and a concomitant increase in net PG release. The Specific Aims of this five-year proposal are to: 1. Develop further the hypothesis that PGT is a PG/lactate exchanger, and define its role in PG release from cells. 2. Define the compartmentation of PG synthetic and degradative pathways in relationship to PGT expression in rat kidney, RMICs, and lung. 3. Characterize PGT isoforms and determine their intracellular expression and transport capacity. 4. Determine the mechanism(s) by which PGT function, PGT protein expression, and PG synthesis are regulated by hypertonicity in RMICs. 5. Examine regulation of PGT expression in the rat kidney in vivo following maneuvers that alter PGE2 production and release.